Suppressors of cytokine signaling (SOCS) have been implicated in regulation of T-cell activation and cytokine-mediated differentiation of T-helper cells. In this study we have characterized the pattern of SOCS expression in naive and activated primary T-helper cells, examined whether expression of SOCS genes is regulated by cytokine or TCR signaling and analyzed the function of SOCS in differentiated T-cells. We show that SOCS1, SOCS2, SOCS3, CIS (cytokine-induced SH2 protein) genes are constitutively expressed in naive T-helper cells, with SOCS3 being the most abundant. Antigen-stimulation of naive T-helper cells down-regulates SOCS3 expression and concomitantly up-regulates SOCS1, SOCS2, CIS genes transcription, suggesting that SOCS genes are differentially regulated by T-cell activation. Down-regulation of SOCS3 expression is subsequently followed by gradual increase in SOCS3 level and corresponding decline in IL-2 secretion. In fact, SOCS3 mRNA levels are inversely correlated with the amount of IL-2 secretion and proliferative responses of differentiating T-helper cells, suggesting mutually antagonistic effects of SOCS3 and IL-2 and feedback regulation of T-cell activation by SOCS3. Furthermore, the degree of SOCS3 inhibition is Ag-concentration-dependent and is mediated in part by Gfi-1, a T-cell transcription factor that regulates S-phase entry in T-cells. Forced over-expression of SOCS3 inhibits proliferation of T-helper cells, while depletion of endogenous SOCS3 by anti-sense SOCS3 cDNA enhances TCR- and cytokine-induced proliferation. Taken together, these results suggest a role for SOCS3 in maintaining T-helper cells in a quiescent state. Transient inhibition of SOCS3 by antigen-stimulation may therefore be essential in allowing activation of resting T-cells.